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Blood Bank

Immunogenicity

When a patient receives a blood transfusion, their immune system may encounter red cell antigens different from their own. Immunogenicity refers to the likelihood that a particular foreign blood group antigen will stimulate the recipient to produce an antibody against it (a process called alloimmunization). This concept is crucial because some antigens, like the D antigen in the Rh system, are highly immunogenic and frequently cause antibody formation, while others rarely do. Understanding immunogenicity helps predict which antigen differences are most likely to lead to clinically significant antibodies, impacting transfusion safety and the potential for future compatibility issues

Immunogenicity: The Power to Provoke

  • Definition: Immunogenicity refers to the relative ability of a specific blood group antigen to stimulate an antibody response (alloantibody formation) when introduced into an individual who lacks that antigen
  • Alloimmunization: The process of forming antibodies against foreign antigens from the same species (e.g., a human forming an antibody to a human blood group antigen they lack)

What Makes an Antigen More Immunogenic?

Several factors contribute, but from a practical blood bank perspective, the key drivers are:

  • Foreignness: The antigen must be recognized as non-self. This is inherent in blood group differences between donor and recipient
  • Chemical Nature & Complexity: Generally, proteins are more immunogenic than carbohydrates because they can be processed and presented by antigen-presenting cells to T-helper cells, leading to a robust IgG antibody response. Large, complex molecules are often better targets
  • Structure & Accessibility: How the antigen is presented on the cell surface matters
  • Dose & Exposure: The amount of antigen introduced (e.g., the number of RBCs transfused) and the frequency of exposure can influence the likelihood and strength of the response

The Immunogenicity Hit Parade: Who Causes the Most Trouble?

Based on decades of transfusion experience, we know some antigens are much more likely to cause alloimmunization than others. Here’s a general ranking of the most clinically significant immunogens encountered in RBC transfusion:

  1. D (Rh System) By far the most immunogenic blood group antigen outside of the ABO system. Studies show that ~80% of D-negative individuals transfused with a single unit of D-positive RBCs will develop anti-D if no preventative measures (like RhIG) are taken. This is why preventing anti-D formation is a cornerstone of transfusion practice
  2. K (Kell System) Considered the most immunogenic after D. While the K antigen has a lower prevalence (~9% in Caucasians), exposure readily stimulates anti-K production in K-negative individuals. Anti-K is a common cause of delayed HTR and HDFN
  3. Other Rh Antigens (c, E, C, e) These protein antigens are also significantly immunogenic, generally ranked in approximately this order of likelihood to stimulate antibody production: c > E > C > e. Matching for these antigens is often considered for chronically transfused patients
  4. Kidd Antigens (Jka, Jkb) Known to be immunogenic. Anti-Jka and anti-Jkb are notorious for causing delayed hemolytic transfusion reactions, partly because the antibody levels can decline over time (making them hard to detect pre-transfusion) but then reappear strongly after re-exposure (anamnestic response)
  5. Duffy Antigens (Fya, Fyb) Moderately immunogenic. Anti-Fya is more common than anti-Fyb and can cause HTR and HDFN
  6. MNS System Antigens (S, s) S and s are significantly more immunogenic than M and N. Anti-S and anti-s can cause HTR and HDFN. (While M and N can stimulate antibodies, anti-M is often naturally occurring IgM and less often clinically significant post-transfusion compared to anti-S/s)

What about ABO? ABO antigens (A and B) are highly immunogenic carbohydrates. However, the “antibodies” (isoagglutinins anti-A and anti-B) are typically naturally occurring. They develop early in life presumably due to exposure to similar carbohydrate structures in the environment (bacteria, food). Therefore, the primary concern with ABO isn’t post-transfusion alloimmunization in the same way as with D or K, but rather the immediate, severe hemolytic reaction if ABO-incompatible blood is transfused due to these pre-existing, potent antibodies

Factors Influencing the Recipient’s Response

It’s not just the antigen – the recipient’s immune system plays a role too:

  • Immune Status: Immunocompromised patients may be less likely to form antibodies
  • Genetic Predisposition: Some individuals seem to be “responders” more prone to making antibodies than others
  • Previous Sensitization: Once sensitized, subsequent exposure leads to a faster, stronger anamnestic response

Clinical Significance: Why We Care

Alloimmunization due to immunogenic blood group antigens is clinically important because the resulting antibodies (usually IgG) can:

  • Cause Hemolytic Transfusion Reactions (HTR): Destruction of transfused red blood cells, leading to anemia, jaundice, fever, and potentially life-threatening complications like shock and renal failure. Can be acute or delayed
  • Cause Hemolytic Disease of the Fetus and Newborn (HDFN): Maternal IgG antibodies crossing the placenta and destroying fetal red blood cells expressing the corresponding antigen inherited from the father
  • Make finding compatible blood difficult: Patients with multiple antibodies or antibodies to high-prevalence antigens pose significant challenges

Managing Immunogenicity in Transfusion Practice

  • ABO/RhD Typing: Standard practice to prevent immediate hemolysis (ABO) and primary anti-D immunization
  • Antibody Screening: Detecting pre-existing antibodies to ensure antigen-negative blood is provided
  • RhIG (RhoGAM): Given to D-negative mothers during pregnancy and after delivery of a D-positive baby (and in other sensitizing events) to prevent the formation of anti-D
  • Prophylactic Antigen Matching: For chronically transfused patients (e.g., sickle cell disease), often matched for Rh (C, E) and K antigens, and sometimes Kidd/Duffy, to prevent alloimmunization to these highly immunogenic antigens

In summary, immunogenicity dictates which blood group differences are most likely to cause problems following transfusion or pregnancy. The D antigen stands out as the most potent, followed by K and other Rh antigens, highlighting the importance of careful donor selection and preventative strategies

Key Terms

  • Immunogenicity: The ability of an antigen to provoke an immune response (antibody formation)
  • Alloimmunization: The process of forming antibodies against antigens from another individual of the same species
  • Alloantibody: An antibody produced against a foreign antigen from the same species
  • Antigen: A molecule (usually protein or carbohydrate) recognized by the immune system
  • Seroconversion: The development of detectable antibodies in the blood serum as a result of infection or immunization
  • Anamnestic Response: A rapid and heightened immune response following re-exposure to an antigen to which the individual has been previously sensitized
  • Hemolytic Transfusion Reaction (HTR): Destruction of transfused red blood cells by recipient antibodies
  • Hemolytic Disease of the Fetus and Newborn (HDFN): Destruction of fetal/newborn red blood cells by maternal antibodies that crossed the placenta
  • RhIG (Rh Immune Globulin): A preparation of concentrated anti-D antibodies given to prevent D-negative individuals from forming their own anti-D after exposure to D-positive red cells